KCC2 Hypofunction Linked to Refractory Seizures

tags: Center for Leukodystrophies

BALTIMORE, August 10, 2018 – Neonatal seizures have an incidence of 3.5 per 1,000 newborns with 50-60 percent of these cases experiencing hypoxic-ischemic encephalopathy (HIE), a form of brain damage that occurs when an infant’s brain does not receive enough oxygen. More than half of the neonatal seizures that occur are refractory, meaning they are resistant to first-line-anti-seizure medications such as phenobarbital (PB 1 .

A recent study at Kennedy Krieger Institute’s Kadam Lab led by Dr. Shilpa Kadam, which appears in Scientific Reports, examined the relationship between refractory seizures and KCC2 hypofunction and found that KCC2 hypofunction contributes to refractory seizures. KCC2 is a neuronal specific chloride co-transporter that helps maintain critical inhibition in the developing brain and with this study presents itself as a novel druggable target for refractory neonatal seizures. Researchers determined that KCC2 positive modulation should be explored as a potential strategy for preventing emergence of refractory neonatal seizures.

“There have been more than 20 anti-seizure drugs introduced to the market in the last several years, but the incidence of refractory seizures has remained stable, which indicates the need for out-of-the-box approaches,” said Dr. Kadam, assistant professor of neurology and the director of the pre-clinical EEG core at Kennedy Krieger. “The clinical field is unsure of how aggressively neonatal seizures should be treated, but this study brings us one step closer to identifying approaches that can prevent refractory seizures in such a fragile patient population. Positive KCC2 modulation is currently an unexplored strategy in the developing brain that could lead to improved and novel strategies for therapeutics and disease modification”

Dr. Kadam’s research team led the study that tested a newly characterized mouse model of ischemic refractory seizures with EEG seizure burdens and documented phenobarbital-resistance similar to those reported in hypoxic-ischemic encephalopathy (HIE). The results from this study will likely lead to future research that will focus on identifying small-molecules that are able to enhance KCC2 function.
About Kennedy Krieger Institute:
Internationally recognized for improving the lives of children and adolescents with disorders and injuries of the brain, spinal cord and musculoskeletal system, Kennedy Krieger Institute in Baltimore, Maryland, serves 24,000 individuals a year through inpatient and outpatient clinics, home and community services, and school-based programs. Kennedy Krieger provides a wide range of services for children with developmental issues, from mild to severe, and is home to a team of investigators who are contributing to the understanding of how disorders develop, while at the same time pioneering new interventions and methods of early diagnosis. Visit KennedyKrieger.org for more information about Kennedy Krieger.
Media Contact:
Jamie Watt Arnold
1. Kang, S. K. & Kadam, S. D. Neonatal Seizures: Impact on Neurodevelopmental Outcomes. Front Pediatr 3, 101 (2015).
Illustration of the new model